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Movement disorders J Neurol Neurosurg : first published as 10.1136/jnnp-2014-309098 on 19 November 2014. Downloaded from

REVIEW Movement disorders in catatonia Subhashie Wijemanne, Joseph Jankovic

▸ Additional material, ABSTRACT between 7.6% and 38% among all psychiatric including videos, is published Catatonia is a complex neuropsychiatric patients.10 The percentage of catatonia due to a online only. To view please characterised by a broad range of motor, speech and general medical condition is reported to range visit the journal online (http:// 11 dx.doi.org/10.1136/jnnp-2014- behavioural abnormalities. ‘Waxy flexibility’, ‘posturing’ from 20% to 39%. Catatonia may be subtle and 309098). and ‘’ are among the well-recognised motor overlooked, which may account for reports suggest- Department of Neurology, abnormalities seen in catatonia. However, there are ing a declining incidence. People with bipolar disor- Parkinson’s Disease Center and many other motor abnormalities associated with ders probably constitute the largest subgroup of Movement Disorders Clinic, catatonia. Recognition of the full spectrum of the catatonic patients.51012In a minority of cases, no Baylor College of Medicine, phenomenology is critical for an accurate diagnosis. cause is found and the current prevalence of idio- Houston, Texas, USA Although controlled trials are lacking pathic catatonia is unknown. Correspondence to are considered first-line therapy and N-Methyl-D- Owing to the wide range of underlying diagnoses, Dr Joseph Jankovic, aspartate receptor antagonists also appears to be patients with catatonia may present as a medical or Department of Neurology, effective. Electroconvulsive therapy is used in those psychiatric emergency13 or develop symptoms ’ Parkinson s Disease Center and patients who are resistant to medical therapy. An during hospitalisation, such as in the intensive care Movement Disorders Clinic, fi Baylor College of Medicine, underlying cause of the catatonia should be identi ed unit (ICU), which can be challenging from a diag- 13 14 6550 Fannin, Suite 1801, and treated to ensure early and complete resolution of nostic standpoint. Catatonia usually presents Houston, TX 77030, USA; symptoms. acutely but may present insidiously, and can be tran- [email protected] sient or chronic, and last for weeks, months and 15 Received 31 July 2014 even years. Catatonic patients are at risk for severe complications such as pneumonia, decubitus ulcers, Revised 8 October 2014 INTRODUCTION Accepted 28 October 2014 malnutrition, dehydration, contractures and throm- Catatonia is a complex neuropsychiatric syndrome Published Online First bosis and delays in diagnosis and management are 19 November 2014 characterised by a broad range of motor, speech and 13 associated with increased morbidity. Although it copyright. behavioural abnormalities. ‘Wa x y flexibility’, ‘postur- may become life-threatening,16 catatonia has an ing’ and ‘catalepsy’ are among the well-recognised excellent prognosis if recognised and treated early. motor abnormalities associated with catatonia. However, there is a wide spectrum of speech and other neurological abnormalities seen in this condi- DIAGNOSTIC CRITERIA AND RATING SCALES tion. This article attempts to summaries the clinical The diagnosis of catatonia is based on clinical obser- features of catatonia; discuss some diagnostic chal- vations. The revised diagnostic criteria were pub- lenges, possible mechanisms and available treatment lished in the fifth Diagnostic and Statistical Manual options in this poorly understood condition. of Mental Disorders (DSM-V) in 2013.17 While the Catatonia was first described by German psycho- DSM-IV used different sets of criteria for diagnosis pathologist Karl Kahlbaum in Die Katatonie oder of catatonia in and primary mood dis- das Spannungsirresein in 1874 as a motor syn- orders versus neurological/medical conditions, the http://jnnp.bmj.com/ drome in patients with behavioural disorders.12 revised DSM-V criteria can be applied across all of He considered catatonia as a distinct clinical entity the different clinical settings. According to DSM-V with progressive symptoms. Catatonia was subse- criteria, to make a diagnosis of catatonia one has to quently classified by psychopathologists Kraepelin have a minimum of 3 of the following 12 clinical and Bleuler as ‘ praecox’ (premature features, either observed or elicited during examin- dementia), a condition which was later classified as ation: (1) mutism, (2) , (3) catalepsy, (4) waxy schizophrenia.3 The uncertainty about its definition flexiblity, (5) agitation, (6) negativism, (7) posturing, was partly responsible for the long-standing neglect (8) mannerisms, (9) , (10) grimacing, on October 2, 2021 by guest. Protected Editor’s choice of catatonia in clinical and scientific literature and (11) , or (12) .17 The criteria Scan to access more 4 free content for its frequent underdiagnosis. It is clear that seem rather arbitrary, and the list of associated fea- catatonia is no longer limited to schizophrenia, and tures highlights the clinical heterogeneity of this that it can be seen in the setting of a variety of neuropsychiatric disorder. other conditions such as psychiatric disorders other Several rating scales have been developed for the than schizophrenia, medical, neurological and sur- assessment of catatonia.18 The Bush-Francis gical conditions, as well as in the setting of certain Catatonia Rating Scale (BFCRS) is the most widely drugs and toxins.567 used scale. This includes 23 items and up to 30 The frequency of catatonia in acute psychiatric signs. Some of the signs (described below) are not admissions is approximately 10%, but estimates listed in the DSM-V criteria, such as excitement, To cite: Wijemanne S, range from 5% to 20% based on diagnostic criteria staring, rigidity, withdrawal, automatic obedience, Jankovic J. J Neurol used in prospective studies conducted during 1–12 impulsivity, ambitendency, grasp reflex, verbigera- Neurosurg Psychiatry months of observation at psychiatric units.489 tion, mitgehen, autonomic abnormality, combative- – 2015;86:825 832. Other surveys have reported a prevalence ranging ness and perseveration.

Wijemanne S, et al. J Neurol Neurosurg Psychiatry 2015;86:825–832. doi:10.1136/jnnp-2014-309098 825 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-309098 on 19 November 2014. Downloaded from

There is also a screening version of BFCRS known as external stimuli, including pain (see online supplementary Bush-Francis Catatonia Rating Screening Instrument (BFCSI), videos 1–3). The positions assumed by the patient may be which contains 14 most common catatonic signs (excitement, unusual and appear uncomfortable to the observer. The patients immobility/stupor, mutism, staring gaze, posturing/catalepsy, can adopt statuesque postures with minimal movement lasting grimacing, echopraxia/echolalia, stereotypes, mannerisms, verbi- for several hours without any apparent fatigue or discomfort. geration, rigidity, negativism, waxy flexibility and withdrawal). Other examples include twisting of the body, standing on one If two or more of the BFCSI signs are present for 24 h or leg like a stork, holding one arm outstretched for a long time, longer, catatonia should be considered as a possible diagnosis. and squatting with extension of arms. Another dramatic postur- To avoid overdiagnosis, signs such as ‘impulsiveness’ and ‘com- ing is the ‘psychological pillow’ where the patient lies in bed bativeness’ were excluded from the screening instrument.19 with the head and shoulder raised as if there is an imaginary Items from the BFCRS are scored on a 0–3 point scale, whereas pillow. The head is raised a few inches above the bed surface items from the BFCSI are scored as ‘absent’ or ‘present’. which is maintained for prolonged period of time. Another catatonia rating scale, the Modified Rogers Scale In negativism there is increasing resistance to passive manipu- (MRS), has also been validated. lation of the limbs which is known as gegenhalten or paratonia. The primary aim of this review is to draw attention to the When eliciting the phenomenon of gegenhalten, it appears to broad spectrum of phenomenology associated with catatonia by the examiner as if the patient is deliberately opposing the highlighting the most characteristic clinical features and provide passive movement.22 Social negativism may include turning illustrative videos. away when addressed, refusing to open the eyes and closing the mouth when offered food or liquids. CLINICAL FEATURES is a common seen in catatonia The catatonic syndrome is seen in two principal forms: hypoki- (see online supplementary videos 1 and 3) which is defined as netic (withdrawn type) or hyperkinetic (excited type).10 Some involuntary, coordinated, patterned, rhythmic, seemingly pur- patients, however, may display features of both types during the poseless movement or utterance performed repeatedly over course of the illness. Patients with hypokinetic or withdrawn time. Some of the motor stereotypies that are seen in catatonia type of catatonia, typically appear awake and watchful, but with include body rocking, shoulder shrugging, hand waving, minimal spontaneous speech and movement. It is commonly opening eye wide and then squeezing them shut, nose wrinkling, associated with mutism, stupor, negativism, obsessional slowness and repetitive mouth and jaw movements. Stereotypies may be and posturing. Hyperkinetic or excited type catatonia is charac- accompanied by self-injurious behaviour, such as head banging, terised by agitation, combativeness, disorganised overproductive self-hitting, punching, biting, kicking and scratching directed at speech (verbigeration), stereotypies, grimacing and echopheno- any body surface. In addition to motor stereotypies patients copyright. mena. There is no difference in the expression of catatonic with catatonia can have phonic stereotypies which include symptoms based on the underlying cause, whether it is psychi- repetitive, apparently meaningless utterances, such as sniffing, atric or medical. clicking, snorting, moaning and other meaningless sounds, Mutism, manifested by minimal or no verbal communication, similar to phonic tics (see online supplementary video 3). These is probably the most frequently observed sign of catatonia in the patients can also have facial grimacing and exaggerated facial acute hospital setting, but the diagnosis is not applicable if there expressions (see online supplementary videos 1–3). is evidence of .20 21 Although typically associated with Mannerisms is another observed clinical feature which is char- hypokinetic catatonia, mutism can also accompany a hyperkin- acterised by repetitive, idiosyncratic movements or gestures that etic movement disorder. Catatonic stupor is manifested by are unique to the individual such as using hands when talking. patient’s absence of movement or other reaction to any stimulus Echophenomena include echopraxia and echolalia. Echopraxia while awake. Patient is typically extremely hypoactive, immobile refers to mimicry of examiner’s movements or imitation of and minimally responsive to stimuli including pain. Stupor can other person’s movements or gestures. Echolalia means nearly http://jnnp.bmj.com/ occur independently or in combination with mutism. simultaneous repetition of words or phrases spoken by others. Differentiating sedation from catatonic stupor can be challen- Catatonic excitement refers to extreme hyperactivity with ging, but the latter is usually associated with normal awake constant motor restlessness which is apparently non-purposeful. EEG.21 Patients with catatonia can go through periods of agita- Although similar, catatonic excitement is different from akathisia tion during which they can injure themselves or others. These in that it does not appear to be associated with a feeling of rest- periods of agitation may be associated with autonomic instabil- lessness and an uncomfortable sensation or an urge to move. ity manifested by hyperthermia, tachycardia and hypertension. Patients with catatonia can have staring gaze where the eyes are Individuals in this excited state may display extreme hyperactiv- focused at a distance with little eye contact (see online supple- on October 2, 2021 by guest. Protected ity with constant motor unrest and purposeless motor activity, mentary video 1). There is little or no visual scanning of envir- and may eventually collapse from exhaustion. onment and there is decreased blinking. One of the most recognisable clinical features of catatonia is Rigidity consists of a stiff position which the patient attempts posturing which refers to spontaneous and active maintenance to maintain despite efforts to be moved. Catatonic rigidity is not of a posture against gravity (see online supplementary videos typically accompanied by cogwheeling or tremor, which helps to 1–3). Waxy flexibility refers the characteristic motor sign of cata- differentiate from parkinsonian rigidity. The state of withdrawal, tonia elicited by the examiner who manipulates the body or also interpreted as ‘social negativism’, is a condition manifested extremities to assume certain postures which the patient can by the patient’s refusal to eat, drink or make eye contact. maintain for a prolong periods of time (see online supplemen- Some patients with catatonia can also demonstrate exaggerated tary videos 1–3). There may be an initial resistance which is cooperation for example, automatically obeying every instruction soon followed by slow release, as if bending a warm candle of the examiner which is known as automatic obedience (see hence the term waxy flexibility.15 Catalepsy refers to the main- online supplementary video 2). Automatic obedience can also tenance of fixed postures in the sitting or standing position for mean the performance of tasks at the command of the examiner prolong periods of time with minimal movement regardless of even though the tasks are inappropriate or dangerous such as by

826 Wijemanne S, et al. J Neurol Neurosurg Psychiatry 2015;86:825–832. doi:10.1136/jnnp-2014-309098 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-309098 on 19 November 2014. Downloaded from reaching into pocket and state: ‘stick out your tongue, I want to original description listed 17 signs, and other authors have prick it with a pin’.19 Mitmachen and Mitgehen are two forms of extended this list, some identifying 40 or more phenomena.15 29 automatic obedience. In Mitmachen the body of the patient can The various phenomenological features are defined differently by be put into any posture, even if the patient is given instructions different authors creating ambiguity and lack of clear definition. to resist. Mitgehen is an extreme form of automatic obedience in The DSM-V list of the various motor and speech abnormalities is which the examiner is able to move the patient’s body with the too vague and it does not capture the true clinical picture of cata- slightest touch, but unlike waxy flexibility the body part immedi- tonia. Very opposing (eg, immobility vs excessive motor activity, ately returns to the original position. This can be tested by asking mutism vs echolalia) or closely similar (eg, posturing vs catalepsy) the patient to extend their arm and then place the examiners motor and speech abnormalities are listed in parallel and are finger beneath the hand and try to raise the arm slowly using given equal diagnostic weight. The published diagnostic criteria gentle push upwards after stating: ‘Do NOT let me raise your and rating scales do not provide sufficient guidance as to how to arm’. When the examiner’s finger retracts the patient’s hand reconcile between different combinations of clinical findings. For moves downward in an attempt to keep in physical contact with example, facial grimacing, phonic stereotypies, echopraxia and the examiner’s finger.19 Catatonic patients can exhibit a great echolalia can be seen not only in patients with catatonia but also deal of impulsivity manifested by suddenly engaging in an in , neuroacanthocytosis, and other inappropriate behaviour such as running down hallway, scream- neurological disorders. This overlap with various disorders indi- ing or taking off clothes without any provocation. Ambitendency cates that catatonia is a symptom or a syndrome with different refers to a state of indecisive or hesitant movement (see online aetiologies rather than a single clinical entity. supplementary video 2). This could manifest as alternating Several studies have examined the discriminative value of cooperation and then resistance in following examiner’s instruc- various catatonia symptoms. One study found that 9 of the 12 tions. One can also elicit the grasp reflex, in which, the patient items that are included in DSM-V possess very high discriminat- forcibly and repeatedly grasps the examiner’s hand when ing value for catatonia, but noted that three items (agitation, offered.22 Verbigeration is the frequent repetition of meaningless stereotypies and mannerisms) had a weak correlation with cata- words and phrases (see online supplementary video 3). Motor tonia. A subsequent study29 found that stereotypies and manner- perseveration is manifested, for example, by persistence of a par- isms also to have high discriminating value for catatonia. ticular movement long after the original command or intent. The lack of single unifying phenotype or a set of highly sensi- Speech perseveration is exemplified by repeatedly returning to the tive and specific diagnostic criteria makes the diagnosis of cata- same topic after it has lost its initial relevance. Catatonic combat- tonia challenging for the clinician, even experienced movement iveness usually occurs in an undirected manner, with no, or only disorder specialist.30 The diagnosis may be especially diffltin a facile explanation afterwards. Autonomic abnormalities include the acute inpatient setting or in the ICU.14 Differentiating cata- copyright. changes in temperature, blood pressure, heart and respiratory tonia from is especially important, as catatonia is rate, and diaphoresis. treated with benzodiazepines whereas delirium may be exacer- bated by . The lack of motor and speech abnor- SUBTYPES OF CATATONIA malities in delirium helps to differentiate it from catatonia. On Malignant catatonia and periodic catatonia are two major sub- the other hand syndrome, central nervous system types of catatonia.23 Malignant catatonia is characterised by infection, autoimmune encephalopathy or some other medical sudden development of intense excitement, delirium, high fever, and neurological conditions encountered in the acute hospital hypertension, catalepsy, mutism, rigidity, stereotypies and pos- setting may overlap with signs of catatonia, and in some cases turing.23 Because of accompanying marked autonomic instabil- necessitate concomitant treatment for both catatonia and the ity and hyperthermia this form of catatonia is potentially underlying condition. In the absence of any clinical, physio- fatal.224The neuroleptic malignant syndrome (NMS) is consid- logical, imaging or other diagnostic markers that are reasonably ered by some as a medication-induced variant of (malignant) sensitive and specificindefining catatonia, the diagnosis rests on http://jnnp.bmj.com/ catatonia.25 Numerous medical conditions leading to malignant the clinical history and observation of characteristic signs. catatonia have been reported. Although randomised clinical trials are lacking, electroconvulsive therapy (ECT) is effective in PATHOPHYSIOLOGY the treatment of malignant catatonia.26 The specific pathophysiological mechanisms underlying catato- Periodic catatonia has a rapid onset and consists of brief, nia are not well understood. Neurochemical studies have recurrent hypokinetic or hyperkinetic abnormalities with epi- focused on the inhibitory neurotransmitter γ-aminobutyric acid sodes lasting 4–10 days which recur over a period of weeks to (GABA) A. The role of GABA in catatonia is supported by the years.27 Patients are generally asymptomatic between episodes, observation of a dramatic response to treatment with benzodia- on October 2, 2021 by guest. Protected but may exhibit inter-ictal facial grimacing, stereotypies and zepines and , both GABA A agonists, in patients with – negativism, particularly late in the course of the illness.28 catatonia.12 31 33 The GABAergic hypothesis is also supported Periodic catatonia is rare and appears to segregate within fam- by the observation that ECT, which is used in drug resistant ilies in an autosomal dominant pattern. There is evidence for catatonia or as a fist-line therapy in malignant catatonia, also linkage to long arm of chromosome 15q15 which was replicated enhances GABA function. Furthermore, the single photon emis- in two independent genome-wide linkage scans based on over sion tomography (SPECT) with iodine-123-iomazenil showed 12 multigenerational pedigrees.28 Overall, periodic catatonia is significantly lower iomazenil binding, an index of benzodiazep- considered to have a better prognosis than the malignant form ine GABA-A receptor density, in the left sensorimotor cortex of of catatonia. patients with akinetic catatonia compared to psychiatric and healthy controls.34 DIAGNOSTIC CHALLENGES There are case series and case reports showing the effectiveness 35 The definition of catatonia both historically as well as in the of N-Methyl-D-aspartate (NMDA)-antagonists in catatonia, DSM-V criteria is very broad. Although only 12 clinical features suggesting that glutamate hyperactivity might be related to are included in the DSM-V diagnostic criteria, Kahlbaum in his catatonic symptoms.36 It has been postulated that NMDA

Wijemanne S, et al. J Neurol Neurosurg Psychiatry 2015;86:825–832. doi:10.1136/jnnp-2014-309098 827 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-309098 on 19 November 2014. Downloaded from hyperactivity causes dysregulation of GABA-A function and that Table 1 Underlying causes of catatonia (other than schizophrenia NMDA antagonists can indirectly restore GABA-A function in and ) the frontal lobes, though more slowly than GABA-A agonists.36 In addition, there is an increased familial transmission in first Infections degree relatives, particularly for periodic catatonia (27%) versus Typhoid fever general catatonia (5%) suggesting a genetic link.37 Several other Neurocysticercosis pathophysiologic models of catatonia have been proposed Prion disease notably motor circuitry dysfunction and a link to epilepsy, endo- Viral crine and immune dysfunction24 but there are insufficient data Subacute sclerosing pan encephalitis to substantiate these hypotheses and further studies are needed. Neurosyphilis Autoimmune and inflammatory AETIOLOGY Systemic lupus erythymatosis or antiphospholipid syndrome* Catatonia can occur in the setting of number of aetiologies Anti-NMDAR encephalitis* (table 1). The disorder is increasingly recognised as a comorbid Paraneoplastic encephalitis syndrome of autism, disorders and patients Multiple sclerosis – with .38 43 In adolescents with autism the Cardiovascular prevalence of catatonia is between 12% and 17%.40 44 It is Takotsubo cardiomyopathy important for clinicians to be aware of the possibility of catato- Renal nia when investigating reasons for the deterioration in skills and Renal failure in dementia with Lewy body disease behaviour occurring in adolescents and adults with autistic spec- Metabolic trum disorders. Wilson’s disease Catatonia is also recognised in the setting of various auto- Hyponatraemia or hypernatraemia immune disorders including anti-NMDA receptor Glucose-6phosphate deficiency (anti-NMDAR) encephalitis,45 that is typically found in young Neurodegenerative disorders women with ovarian teratomas, but can be also encountered in Westphal variant of Huntington’s disease men and in adults aged 45 years and above.46 The encephalitis is Parkinson’s disease less severe in patients aged ≥45 years than in young adults, but Familial the outcome is poorer in older patients, partly because of delays CNS in diagnosis and treatment. Anti-NMDAR encephalitis typically Posterior reversible encephalopathy begins with a prodrome of a febrile, flu-like illness, which is fol- Subdural hematoma copyright. lowed by a spectrum of neuropsychiatric sequelae such as behav- Pontine and extrapontine myelinolysis ioural and cognition symptoms, memory deficit, , , seizures, dysautonomia and hypoventilation.47 Hematology Movement disorders associated with anti-NMDAR encephalitis Pernicious anemia include chorea, athetosis, stereotypies (particularly involving the Thrombotic thrombocytopenic purpura orofacial region), dystonia, ataxia, facial and limb myorhythmia, Psychiatric and opisthotonus. The exact prevalence of catatonia in Autism* anti-NMDAR encephalitis is unknown but many patients exhibit Alcohol withdrawal physical manifestations consistent with catatonia which may Medications include mutism, facial and limb stereotypies, facial grimacing, Venlafaxine-associated hyponatraemia staring episodes, waxy flexibility and posturing among Pegylated interferon-α 2b and ribavirin for hepatitis C others.45 48 Treatment of this condition is mainly focused on withdrawal http://jnnp.bmj.com/ tumour resection and immunotherapy. However, when asso- Paliperidone palmitate ciated with catatonia it can be underdiagnosed and inadequately Dexamethasone treated. A treatment algorithm which includes management of Zolpidem withdrawal catatonia was recently published.49 Other autoimmune encephal- Temazepam withdrawal opathies such as systemic lupus erythematosus and antiphospho- Quinolones lipid syndrome as well as infectious encephalitis can also present Clozapine withdrawal* with catatonia50 (table 1). Manganese neurotoxicity Clonazepam/benzodiazepine withdrawal on October 2, 2021 by guest. Protected TREATMENT Ziprasidone Before discussing various treatment strategies in catatonia it is Lithium toxicity important to note that many recommended treatments have not Tramadol and meperidine been subjected to rigorous, controlled trials. Furthermore, the Azithromycin currently available rating scales, such used to monitor response Levetiracetam to treatment, as the BFCRS, lack the sensitivity necessary to Efavirenz measure minimal clinically meaningful improvements.18 One of Surgical causes the challenges in using rating scales is that catatonic symptoms Liver or kidney transplantation* fluctuate over time and may require longer periods of observa- Renal transplant tion to obtain the full clinical picture. While the patient is been Temporal lobectomy treated for catatonia it is also very important that an underlying Continued aetiological cause is searched and treated without delay.

828 Wijemanne S, et al. J Neurol Neurosurg Psychiatry 2015;86:825–832. doi:10.1136/jnnp-2014-309098 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-309098 on 19 November 2014. Downloaded from

treatments for catatonia with variable and poorly documented Table 1 Continued success (table 2). Deep brain stimulation surgery Neuroleptics, particularly typical , are generally Burns not recommended as treatment for acute catatonia, even for cata- Trauma tonic episodes due to schizophrenia.2 Indeed, there is some evi- Other causes dence that classic antipsychotics may precipitate malignant Cyber bulling catatonia and NMS, underscoring again the importance of cor- Deprivation, abuse or trauma in pediatric population rectly diagnosing the disorder.26 58 This is an important issue in Pregnancy or postpartum treating patients presenting with psychosis and catatonia. The lit- Down syndrome erature on the use of atypical antipsychotics in catatonia consists Wasp sting of case reports and retrospective studies.58 One retrospective *Most frequently reported causes of catatonia. study found that clozapine stood out uniquely as an Anti-NMDAR, anti-N-Methyl-d-aspartate; CNS, central nervous system. agent that was uniformly beneficial. There are several case reports showing benefit with olanzapine. Quetiapine has also Benzodiazepines are widely considered the first-line treatment been used in patients with acute catatonic schizophrenia with for catatonia, which can provide a rapid and dramatic improve- good outcome as well as risperidone.59 ment in symptoms51 52 (table 2). ECT has long been known to be particularly effective for cata- There are no double-blind randomised controlled trials docu- tonia, regardless of the aetiology.260Although there is lack of menting the efficacy of benzodiazepine in catatonia.53 The evi- data from randomised clinical trials supporting its efficacy and dence comes from a number of case series and case reports which safety, ECT has been shown to be effective in cases of medication document a response rate of 60–80%.2612Among the benzodia- refractory catatonia. A retrospective study involving 27 patients zepines, lorazepam is often selected as the drug of choice, which (85% were resistant to medical therapy), 59% improved with can be administered orally or parenterally. An open trial involv- ECT, especially younger patients with autonomic dysregula- ing 13 acute catatonic patients, 2 mg of intravenous lorazepam tion.61 Authors concluded that daily administration of ECT may reduced catatonia scores on the BFCRS by 60% within 10 min.12 be more effective, whereas longer duration of seizure activity at The typical starting daily dose is 3 mg/day which can be titrated the final ECT session was related to better response to ECT.61 In up as necessary. Dosages of 20–30 mg/day in divided doses are order to provide more lasting improvement, daily treatments occasionally necessary and the response can be quite dramatic. for2–5 days may be required.62 There are other studies showing Within 3 h of receiving lorazepam 1–3 mg sublingually or intra- effectiveness of ECT to range from 85% to 93% in catatonia muscularly, the vast majority of catatonic patients, who have been patients.63 In a retrospective study involving 63 patients with copyright. immobile, mute, withdrawn and refusing to eat or drink, enjoy catatonia, the fast responders were the ones with a shorter dur- complete release from their symptoms. Once the troublesome ation of illness illustrating the fact that early detection of illness symptoms are controlled the effective dose of lorazepam that plays a crucial role in treatment response.63 In the same study, achieved a complete resolution of the catatonic signs should be participants with waxy flexibility and gegenhalten showed a maintained for several days until the underlying cause of catato- faster response rate, while participants with echophenomena nia is found and appropriately treated.54 showed a slower response.63 Although there are no absolute con- Intravenous test dose of lorazepam (1–2 mg) can also be used traindications to ECT, this treatment intervention should not be as a diagnostic test for catatonia.655The reduction or the full considered first-line therapy except for life-threatening malignant relief of catatonia symptoms within a few minutes is diagnostic. catatonia.262Mortality in malignant catatonia may increase if Absence of the response, however, does not rule out the diagno- ECT is not begun within 5 days of symptom onset.15 Some cases sis of catatonia as approximately 20% of participants do not of catatonia may require maintenance ECT to prevent recurrent respond to such a challenge.12 While benzodiazepines are safe episodes. Although controlled trials are lacking the effectiveness http://jnnp.bmj.com/ medications when used in the short term, several issues should of benzodiazepines and ECT in anti-NMDAR encephalitis and be kept in mind during treatment such as sedation and the risk other paraneoplastic encephalitis has been well documented.45 39 of hypoventilation in patients with obesity, or those with Fast repetitive transcranial magnetic stimulation of the left obstructive sleep apnoea, falls in elderly patients or those with dorsolateral prefrontal cortex was also reported to be effective balance problems.54 in two case reports (10 Hz)64 Although the long-term outcome Zolpidem (10 mg/day), a non-benzodiazepine GABA agonist of catatonia has not been rigorously studied, catatonia appears of the imidazopyridine class that potentiates GABA by binding to have a generally favourable prognosis.2 to GABA-A receptors at the same location as benzodiazepines on October 2, 2021 by guest. Protected was reported to improve catatonic symptoms.32 Zolpidem is SUMMARY increasingly recognised as another pharmacological treatment Catatonia is a neuropsychiatric disorder that encompasses a wide option for catatonia and is even suggested as an effective and range of movement disorders. As there is no catatonia-specific prompt pharmacological test for catatonia.56 biomarker, recognition of the characteristic clinical features is NMDA receptor antagonists have been shown to be effective critical to the diagnosis. Catatonia is no longer considered a in catatonia based on case series and multiple care reports.35 36 subtype of schizophrenia and can be seen in the setting of other and which exert NMDA receptor antag- psychiatric disorders, general medical, neurological and surgical onist effect are reported to be effective in catatonia.36 conditions, as well as drugs and toxic substances. The underlying Amantadine doses from 100 up to 400 mg/day have been used pathophysiological mechanisms are still not clear and a ‘GABA and memantine 10 mg/day up to 20 mg/day have been shown to hypothesis’ has been proposed. Most patients respond well to be effective.36 Memantine, unlike amantadine, has no significant benzodiazepines or ECT and prompt treatment in the early effects on neurotransmission.36 57 Other medications, phases of catatonia is important for the best outcome. The exact including , , tetrabenazine, corticosteroids prevalence of idiopathic catatonia is unknown. However it is and rituximab have all been used as either primary or adjunctive important that an underlying cause of the catatonia is identified

Wijemanne S, et al. J Neurol Neurosurg Psychiatry 2015;86:825–832. doi:10.1136/jnnp-2014-309098 829 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2014-309098 on 19 November 2014. Downloaded from

Table 2 Studies on treatment of catatonia Medication Type of study Conclusion

Lorazepam A randomised, double-blind, Not effective in chronic schizophrenia with catatonia Ungvari et al31 placebo-controlled cross-over study of 18 patients Lorazepam/ECT Prospective study of 28 patients Sixteen of the 21 who completed treatment showed benefit. Four patients that Bush et al12 failed lorazepam responded to ECT Lorazepam Retrospective study of 107 Thirty two of 99 (32.3%) showed response (with complete resolution of Tibrewal et al55 catatonic symptoms). Improvement in catatonic symptoms was seen in 68 of 99 (68.7%) patients Lorazepam-diazepam Retrospective study of 21 patients Among 21 patients 13 (61.9%) patients responded within 2 h, 18 (85.7%) Lin and Huang52 responded within 1 day, and all became catatonia-free within a week Lorazepam-diazepam Retrospective study of 12 patients Eight patients complete remission (one dose of 2 mg lorazepam intramuscularly Huang et al65 (IM)). Two patients needed two doses of 2 mg lorazepam IM. Two patients failed lorazepam but responded to one dose of 10 mg diazepam intravenous. All catatonic features remitted in 24 h with 100% response rate Lorazepam and risperidone Case reports Effective in two case reports Grenier et al66; Prakash et al67 Zolpidem Case series 12 patients Zolpidem was used as a diagnostic test in 6 out of the 12 patients. Response Cottencin et al33 was seen in 4 and no response in 2 patients Zolpidem Case report Effective in case report Peglow et al32 Amantadine Case series five patients Effective in case series de Lucena et al35 Amantadine Case reports Effective in case reports Hervey et al68; Ene-Stroescu et al69 Amantadine/memantine Case reports 25 patients Effective in case reports Memantine Case report Effective in case report Obregon et al57 Topiramate Case series 4 patients Effective in case series McDaniel et al70

Olanzapine or clozapine Case reports and case series Effective in case reports and case series copyright. Nicolato et al71; Chang et al72; Spiegel73; Chattopadhyay et al74; Ueda et al75 Olanzapine and amantadine Case report Effective in case report Babington et al76 Quetiapine Case series 39 patients Effective in case series Yoshimura et al77 Risperidone Case reports Effective in case reports Kopala et al78; Hesslinger et al59 ECT Retrospective study 63 patients Response to ECT was noticed in 56 out of 63 patients (88.89%). Raveendranathan et al63 ECT Retrospective study 27 Improvement was seen in 16 (59%) patients van Waarde et al61 ECT Retrospective study with 22 patients Improvement was seen in 26 out of 28 cases (93%) Rohland et al79 http://jnnp.bmj.com/ ECT and olanzapine Case report Effective in case report Tan et al80 ECT, electroconvulsive therapy.

and treated to ensure early and complete resolution of symptoms. NeuroTechnologies; Huntington’s Disease Society of America; Huntington Study on October 2, 2021 by guest. Protected Further studies are clearly needed to help better characterise the Group; Ipsen Limited; Kyowa Haako Kirin Pharma, Inc (istradefylline); Lundbeck Inc clinical features and to improve our understanding of the patho- (tetrabenazine); Medtronic; Merz Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; National Institutes of Health; National Parkinson Foundation; physiology of this unique condition with the aim to develop Omeros Corporation (OMS824); Parkinson Study Group; Pharma Two B; Prothena pathogenesis-targeted preventive therapies and better symptom- Biosciences Inc (PRX002); Psyadon Pharmaceuticals (ecopipam), Inc; St. Jude atic treatments. Medical; Teva Pharmaceutical Industries Ltd; UCB Inc; University of Rochester; Current consultant or an advisory committee member: Allergan, Inc; Auspex Pharmaceuticals, Inc; Ipsen Biopharmaceuticals, Inc; Lundbeck Inc; Teva Pharmaceutical Industries Ltd. Royalties: Cambridge; Elsevier; Future Science Acknowledgements The authors would like to thank Dr Amber Stocco for Group; Hodder Arnold; Lippincott Williams and Wilkins; Wiley-Blackwell. During providing online supplementary videos 2 and 3 that accompany this manuscript. the past 2 years JJ has served on the following editorial boards and foundation Contributors SW involved in the manuscript preparation, writing of the first draft. advisory boards: Editorial boards: Medlink: Neurology; Expert Review of JJ involved in the manuscript review and critique. Neurotherapeutics; Neurology in Clinical Practice; The Botulinum Journal; PeerJ; Therapeutic Advances in Neurological Disorders; Neurotherapeutics; Tremor and Competing interests JJ has no competing interests but during the past 2 years ’ has received: Current Research and Center of Excellence Grants: Adamas Other Hyperkinetic Movements; Journal of Parkinson s Disease; UpToDate. Pharmaecuticals, Inc (amantadine); Allergan, Inc (botulinum toxin); Auspex Speakers Bureau: none; Stock Ownership: none. SW has no competing interests. Pharmaceuticals, Inc (SD809); CHDI Foundation; GE Healthcare; Great Lakes Provenance and peer review Not commissioned; externally peer reviewed.

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